“Fine-Mapping of an Expanded Set of Type 2 Diabetes Loci to Single-Variant Resolution Using High-Density Imputation and Islet-Specific Epigenome Maps”, Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason M. Torres, N. William Rayner, Valgerdur Steinthorsdottir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael Preuss, Bram Peter Prins, Xiuqing Guo, Lawrence F. Bielak, DIAMAN T. E. Consortium, Amanda J. Bennett, Jette Bork-Jensen, Chad M. Brummett, Mickaël Canouil, Kai-Uwe Eckardt, Krista Fischer, Sharon L. R. Kardia, Florian Kronenberg, Kristi Läll, Ching-Ti Liu, Adam E. Locke, Jian′an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Sch࿆nherr, Claudia Schurmann, Loïc Yengo, Erwin Böttinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, Jose C. Florez, Ian Ford, Oscar H. Franco, Timothy Frayling, Vilmantas Giedraitis, Sophie Hackinger, Andrew Tym Hattersley, Christian Herder, M. Arfan Ikram, Martin Ingelsson, Marit E. Jørgensen, Torben Jørgensen, Jennifer Kriebel, Johanna Kuusisto, Symen Ligthart, Cecilia M. Lindgren, Allan Linneberg, Valeriya Lyssenko, Vasiliki Mamakou, Thomas Meitinger, Karen L. Mohlke, Andrew D. Morris, Girish Nadkarni, James S. Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Daniel R. Witte, Josée Dupuis, Patricia A. Peyser, Eleftheria Zeggini, Ruth Loos, Philippe Froguel, Erik Ingelsson, Lars L. Lind, Leif Groop, Markku Laakso, Francis S. Collins, J. Wouter Jukema, Colin Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Gonçalo Abecasis, James B. Meigs, Jerome I. Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J. Wareham, Kari Stefansson, Anna L. Gloyn, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy2018-01-09 (, ; similar)⁠:

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ~27M variants (~21M with minor allele frequency [MAF]<5%), identified 243 genome-wide statistically-significant loci (p<5×10−8; MAF 0.02%–50%; odds ratio [OR] 1.04–8.05), 135 not previously-implicated in T2D-predisposition.

Conditional analyses revealed 160 additional distinct association signals (p<10−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF<5%) and 24 rare (MAF<0.5%) index SNPs at 60 loci, including 14 with estimated allelic OR>2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localization of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease.

Genome-wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9× in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.